Apolipoprotein E (ApoE) is a 299 amino acid with an expanding role in the neurobiology of human disease. There are three common human isoforms of apoB, designated E2, E3, and E4 which differ by single amino acid interchanges. The apoE4 isoform has been associated with increased susceptibility to late onset familial and sporadic Alzheimer's disease (AD) as well as poor outcome after a variety of acute neurological insults, including intracranial hemorrhage, stroke, closed head injury and cardiopulmonary bypass. In cell culture models, we have demonstrated that apoE downregulates glial activation and suppresses release of inflammatory mediators and reactive oxygen species. One unifying hypothesis that explains the role of apoE in acute and chronic neurological disease is that it binds to specific glial cell surface receptors to downregulate their state of activation. We have created peptides derived from the receptor-binding region of the apoE ligand that mimic the suppressive effects of the entire apolipoprotein-B molecule. In Phase 1, we will create progressively smaller peptides derived from this receptor binding region to determine the smallest peptide that retains the pharmacological activity of suppressing glial activation and promoting neuronal viability. This bioassay will be used to identify small candidate peptides that potentially protect neurons in the setting of acute brain injury and neurodegenerative disease. PROPOSED COMMERCIAL APPLICATIONS: We will identify peptides derived from the apoE-ligand's receptor binding region that have potential neuroprotective activity based on our bioassay of glial activation and neuronal viability. These peptides and peptides modified to cross the blood-brain barrier will be tested in animal models of acute brain injury. These peptides will provide an important proof-of- principle for novel drugs with therapeutic potential in acute brain injury and neurodegenerative disease. Once successful, non-peptido-mimetics of these peptides will be developed.